Apo CIII is one of ten apolipoproteins that form the lipoprotein particles responsible for transporting cholesterol and triglyceride throughout the body. Apolipoproteins function to regulate the synthesis and catabolism of the different classes of lipoproteins, and as such are important determinants of plasma cholesterol and triglyceride levels. Elevated plasma lipids are a significant risk factor for atherosclerosis, the leading cause of heart disease. Apo CIII is associated primarily with triglyceride rich lipoprotein particles, and physiological evidence indicates that it plays an important role in regulating plasma triglyceride levels. Recent studies with transgenic mice that over-express CIII, demonstrate that CIII production rate is an important determinant of plasma triglyceride levels. These results present the possibility that the transcriptional regulation of the CIII gene could play a significant role in modulating plasma triglyceride levels. Several lines of evidence suggest that the CIII gene is regulated in response to physiological signals that are also associated with changes in lipoprotein levels. Preliminary results demonstrate that several intercellular messengers known to have an effect on plasma triglyceride metabolism (glucocorticoids and cytokines that mediate cellular responses to inflammation), after CIII transcriptional activity in cultured hepatocytes. In addition, the CIII promoter contains several transcription regulatory elements that have been implicated in the induction of gene expression by a variety of stimuli. Taken together, these results present the possibility that CIII gene expression is regulated by physiological signals and that this regulation plays a significant role in the modulation of plasma triglyceride levels. The overall goal of the proposed research is to understand the molecular mechanisms that regulate apo CIII gene expression, and to elucidate the role that this regulation plays in modulating lipoprotein metabolism. The specific aims are to: 1) Identify physiological signals (hormones and cytokines) that modulate CIII gene transcription in tissue culture cells, 2) Characterize the transcriptional regulatory elements and protein factors that are responsible for the modulation of CIII gene expression by cytokines and hormones, and 3)Analyze the regulation of CIII gene expression and its relationship to lipoprotein metabolism in normal and transgenic mice. Results generated from these experiments will provide valuable insights into the potentially crucial role of CIII transcriptional regulation in the modulation of plasma triglyceride levels, and will increase our understanding of how physiological signals like hormones and cytokines modulate transcription.